Ibrutinib (CAS: 936563-96-1) is a first-in-class, potent, orally administered covalently-binding inhibitor of BTK. It is a potent inhibitor of BTK that binds covalently to Cys-481 in the active site of BTK, resulting in inhibition of kinase activity.

Indications

Ibrutinibis a kinase inhibitor indicated for the treatment of adult patients with:

Mantle cell lymphoma (MCL) who have received at least one prior therapy (1.1) ;

Upon verification and description of clinical benefit in a confirmatory trial;

Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL);

Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion;

Waldenstr?m's macroglobulinemia (WM);

Chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.

Mechanism of Action

Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.

Side effects

The most common adverse reactions (≥30%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) are thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and bruising. The most common adverse reactions (≥20%) in patients with cGVHD are fatigue, bruising, diarrhea, thrombocytopenia, muscle spasms, stomatitis, nausea, hemorrhage, anemia, and pneumonia.

Drug interactions

Potentially hazardous interactions with other drugs:

Anti-arrhythmics: concentration possibly increased by amiodarone and dronedarone - avoid or reduce dose of ibrutinib.

Antibacterials: concentration possibly increased by ciprofloxacin, clarithromycin, erythromycin and telithromycin - avoid or reduce dose of ibrutinib; concentration reduced by rifampicin - avoid.

Antidepressants: concentration possibly reduced by St John's wort - avoid.

Antiepileptics: concentration possibly reduced by carbamazepine, fosphenytoin, phenobarbital and phenytoin - avoid.

Antifungals: concentration possibly increased by fluconazole, itraconazole, ketoconazole and voriconazole - avoid or reduce dose of ibrutinib.

Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.

Antivirals: concentration possibly increased by atazanavir, darunavir, fosamprenavir, indinavir, ritonavir and saquinavir - avoid or reduce dose of ibrutinib.

Aprepitant: concentration possibly increased - avoid or reduce dose of ibrutinib.

Calcium channel blockers: concentration possibly increased by diltiazem or verapamil - avoid or reduce dose of ibrutinib.

Cobicistat: concentration possibly increased, avoid or reduce dose of ibrutinib.

Cytotoxics: concentration possibly increased by crizotinib - avoid or reduce dose of ibrutinib; concentration possibly increased by imatinib - reduce dose of ibrutinib.

Grapefruit juice and Seville oranges: avoid.